E-DRUG: Two recent articles about Cancer medicines and the WHO Model list of Essential Medicines
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[Thank you Richard for the very comprehensive and helpful analysis of these two articles. Warning - long message. BS]
Hi E-Druggers,
There have been two recent articles about cancer medicines and the WHO Model List of Essential Medicines. These have been in JAMA and Lancet Global Health. I do hope that E-Druggers will read these two articles in JAMA and Lancet Global Health and comment on E-Drug. I provide reference details below and if you are unable to download the article I can send you electronic copies for your personal use.
The first in the Journal of the American Medical Association is a short Viewpoint article by three authors from Harvard Medical School.
Title: Reforming the World Health Organization's Essential Medicines List Essential but Unaffordable
Authors: Thomas J. Hwang, MD1,2 Aaron S. Kesselheim, MD, JD, MPH2
Kerstin N. Vokinger, MD, JD, PhD2,3
Reference: JAMA. 2022;328(18):1807-1808. doi:10.1001/jama.2022.19459 October 24, 2022
available at
https://jamanetwork.com/journals/jama/fullarticle/2797965
It is available free but you have to register.
There is no abstract for the article so I will summarize it briefly.
The authors briefly introduce the history of the WHO Model List of Essential Medicines (WHO MEML) and state that the selection of medicines for the list has been increasingly complicated by the increasing cost of new drugs entering the market.
The authors make a proposal to remove cost and cost effectiveness from consideration by the WHO Expert Committee. They provide information about two categories of cancer medicines, Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) immune checkpoint inhibitors that were considered at the 2021 Expert Committee meeting but were rejected.
They suggest that because one of these products, Pembrolizumab, is recommended by both the US National Comprehensive Cancer Network and European Society for Medical Oncology (ESMO) clinical practice guidelines; that these products should have been included without considering the cost.
They also discuss the rejection of pertuzumab in combination with trastuzumab and taxane chemotherapy for first-line treatment of ERBB2 (formerly HER2)-positive unresectable or metastatic breast cancer.
They summarize their proposal as follows:
"For future iterations of the Essential Medicines List, WHO should formally separate its expert committee reviews of comparative effectiveness, safety, and public health priority from consideration of the price of medicines and their cost-effectiveness."
Later they justify this suggestion by stating:
"...having a 2-stage, independent approach that separates clinical and economic reviews, as is currently done by health technology assessment agencies in France, Germany, and several other countries, could provide a more robust and reproducible basis for establishing the list."
These are the key points that I got from the opinion piece.
But I disagree with their proposal. I looked at the application for the 2021 meeting and it is deficient in many areas.
The application is available at
https://cdn.who.int/media/docs/default-source/essential-medicines/2021-eml-expert-committee/applications-for-addition-of-new-medicines/a.1_anti-pd1-ici.pdf?sfvrsn=8b1482fc_8
The application was submitted by a representative from the European Society for Medical Oncology (ESMO). The application failed to respond to a number of the sections in the application form. For example the section 5 on International availability - sources, if possible, manufacturers and trade names the applicants respond by saying
"In this submission, we will consider the indications for ICIs in NSCLC scored as European Society for Medical Oncology- Magnitude of Clinical Benefit Scale (ESMO-MCBS) grade 4 or 5 in Non-Curative settings and for which no controversies exist."
They then provided details of how the different products are recommended for use.
In response to the question about:
Information supporting the public health relevance of the application. They point out that lung cancer is common. They then state that targeted therapies have redefined the therapeutic landscape for a particular subtype of these molecularly druggable cancers.
What does this mean? They give as an example "(e.g. epidermal growth factor receptor [EGFR] mutations, anaplastic lymphoma kinase [ALK] rearrangements, ROS1 rearrangements, BRAF mutations, HER2 mutations or amplifications, NTRK1-3 fusions)" and they then say ", these therapies are ineffective in those tumours lacking such genetic alterations, the majority of NSCLC patients."
What they do not say is how many countries could detect these lung cancers that could be treated!
In their response to the question about Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group. They state
"The cost-effectiveness studies published for ICI frequently exhibit some aspects that are worth being recognised: Often, HTA, governmental, and independent CE analysis in the literature were not updated according to the recent and mature OS benefit data. For instance, NICE analysis and decisions commonly reflected the uncertainty of OS immature data from interim analysis, where the CE threshold was not favourable to the medicine adoption considering the price negotiations.
Some of those analyses occurred before the updated OS mature data, and further analysis will be required for the appraisal committee decision. Far beyond a comprehensive CE analysis, finance as one of the pillars for UHC goal also requires budget impact analysis, and the costs related to the investment for maintenance, and improvement to offer quality and timely diagnosis, the most appropriate treatment, and the expected follow up in terms. To deliver such tasks, workforce, capacity building, are also components to guarantee a feasible and universal access to medicines." But no data from non OECD countries is provided.
So I believe that the 2021 Expert Committee was correct to reject this application.
I believe that the Hwang JAMA viewpoint article fundamentally misunderstands the role of the Expert Committee in recommending which products should be included in the WHO MEML. The expert Committee is not asked to evaluate which medicines are efficacious for common conditions of public health concern. That is a prerequisite for consideration. The committee is asked to prepare a model list to guide decision makers in Low and Middle Income countries as to which medicines that should try to make available to their populations.
The criteria used includes public health need taking into account the availability and costs of diagnosing these conditions, clinical effectiveness under real world conditions not clinical trial efficacy studies alone, safety, comparative cost and cost effectiveness within the therapeutic class, regulatory status, availability of Pharmacopeial standards and the proposed text for the WHO Model Formulary.
The committee is tasked with reviewing all aspects of an application and then balancing all the factors to make a judgement that is published to advise individual authorities. Governments are not bound to follow the WHO Model List. Every country makes their own decisions! Cost and comparative cost effectiveness are just another set of considerations for the committee to consider. Separating the functions of the committee into two streams will complicate and delay decision making by the WHO.
The second article is in Lancet Global Health 2022; 10: e1860-66 Published Online September 29, 2022 https://doi.org/10.1016/ S2214-109X(22)00376-X
Here is the title, authors and abstract
Cancer medicines on the WHO Model List of Essential Medicines: processes, challenges, and a way forward
by Kristina Jenei, Zeba Aziz, Christopher Booth, Bernadette Cappello, Francesco Ceppi, Elisabeth G E de Vries, Antonio Fojo, Bishal Gyawali, Andre Ilbawi, Dorothy Lombe, Manju Sengar, Richard Sullivan, Dario Trapani, Benedikt D Huttner, Lorenzo Moja
Abstract: The selection of cancer medicines for national procurement requires deliberate evaluation of population benefit, budget impact, sustainability, and health system capacity. However, this process is complicated by numerous challenges, including the large volume and rapid pace of newly developed therapies offering marginal gains at prohibitively high prices. The WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc) have undergone a series of evidence-based updates to ensure recommended cancer medicines offer meaningful clinical benefit.
This Health Policy paper describes how cancer medicines are listed on the EML and EMLc, including two updated WHO processes:
(1) the formation of the Cancer Medicines Working Group, and
(2) additional selection principles for recommending cancer medicines, including a minimum overall survival benefit of 4-6 months with improvement to quality of life compared with standard treatment.
These updates, along with proposals to include formal price considerations, additional selection criteria, and multisectoral collaboration (eg, voluntary licensing) promote procurement of high-value essential cancer medicines on national formularies in the context of supporting sustainable health systems to achieve universal health coverage.
Available at https://www.thelancet.com/action/showPdf?pii=S2214-109X(22)00376-X
This is a very different paper. It is much longer and is written by WHO staff members and a number of cancer experts from around the world though there is only one author from a Low or Middle Income country.
The authors describe the history of how WHO has attempted to address the inclusion of cancer medicines on the WHO-MEML. The authors describe how the WHO Expert Committee on selection and use of Essential medicines established a Cancer Medicines Working Group in 2017 to advise the Expert committee.
This led to the Expert Committee accepting the recommendation of the Working Group to use the ESMO Magnitude of Clinical Benefit Scale to identify high value cancer medicines worth considering for addition to the WHO Model List.
They also adopted a survival benefit threshold of 4-6 months as a pre requisite for inclusion. Other criteria for consideration for inclusion of cancer medicines are also discussed in the article.
These include disease stage and line of therapy, health system feasibility, and prices. They end the article by suggesting a way forward. Their final sentence reads
"The endorsements of a minimum threshold for overall survival gain, use of the ESMO-MCBS tool, and concurrent proposals to include formal price considerations and additional selection principles, ensure cancer medicines recommended for inclusion on the WHO EMLs offer maximum overall survival benefit and are sensitive to associated health system impacts."
This is an important paper that lays out how WHO is attempting to address this challenging issue. This is an issue that LMICs have to struggle with and taking this article as a starting point countries may wish to discuss this topic and develop criteria and processes for how they will make these difficult decisions.
For me personally, when I worked on the Zimbabwe Essential Drugs Action Programme in the late 1980s I was a member of the Oncology Committee that addressed these issues. The committee published an article in Health Policy and Planning in 1980 titled Rational Use of cytotoxic drugs in a developing country. The article is available at https://academic.oup.com/heapol/article-abstract/5/4/378/559364 .
I do hope that E-Druggers will read these two articles in JAMA and Lancet Global Health and comment on E-Drug.
Richard Laing
Retired Professor, Department of Global Health
Boston University School of Public Health,
E mail richardl@bu.edu